Antidiabetic formulation and method

ABSTRACT

An antidiabetic pharmaceutical formulation is provided, especially adapted for treating Type II diabetes, which includes a combination of metformin and glipizide in a manner to control moisture in the formulation so that the glipizide does not hydrolyze, yet the metformin is compressible, if necessary. A method for treating diabetes is also provided employing the above formulation.

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical formulation and methodfor treating type 2 diabetes. The formulation includes metformin andglipizide (a sulfonyl urea) in a manner to control moisture in theformulation so that the glipizide does not hydrolyze, yet the metforminis compressible, if necessary.

BACKGROUND OF THE INVENTION

The biguanide antihyperglycemic agent metformin disclosed in U.S. Pat.No. 3,174,901 is currently marketed in the U.S. in the form of itshydrochloride salt (Glucophage®), by the Bristol-Myers Squibb Company.

The diagnosis and management of type 2 diabetes mellitus is rapidlyundergoing progressive changes. It is now widely accepted that glycemiccontrol makes a difference. The goal of diabetes therapy today is toachieve and maintain as near normal glycemia as possible to prevent thelong-term microvascular and macrovascular complications of an elevatedblood glucose. The diagnosis of diabetes has undergone significantchanges as evidenced by the new ADA diagnostic and classificationguidelines. Oral therapeutic options for the treatment of type 2diabetes mellitus, until recently, have been severely limited. Prior to1995, sulfonyl ureas had been the mainstay of oral diabetes agents inthe United States. Sulfonyl ureas target one mechanism of hyperglycemiaby augmenting insulin secretion from the beta cell. Since 1995, threenew classes of agents have been added to the anti-diabetes armamentariumfor the management of hyperglycemia. Metformin, a biguanide, targetsadditional mechanisms of hyperglycemia by inhibiting hepatic glucoseproduction and enhancing peripheral glucose uptake and thereby reducinginsulin resistance; thiazolidinediones such as troglitazone,rosiglitazone and pioglitazone decrease peripheral insulin resistance;and alpha-glucosidase inhibitors such as acarbose and miglitol helpcontrol postprandial glucose excursion by delaying absorption of dietarycarbohydrate. These agents are all indicated as monotherapy and some areindicated for use in combination therapy, generally after monotherapyhas been found to be inadequate.

In 1995, metformin was added to sulfonyl urea therapy in patients whohad not achieved glycemic control with sulfonyl urea monotherapy, andthe two agents were found to have a remarkable effect on glycemiccontrol or lowering of hemoglobin-A1c. The different mechanisms ofaction in targeting hyperglycemia are complimentary and make combinationuse attractive and a rational course of action. Prescription datareveals approximately 60% of metformin use is in combination with asulfonyl urea.

Examples of combinations of metformin and the sulfonyl urea glyburide(also referred to as glibenclamide) are disclosed in documents such asthe following:

(1) WO 97/17975 published May 22, 1997, (Barelli et al, Istituto GentiliS.P.A.) and U.S. Pat. No. RE37,330E (hereinafter Barelli et al)discloses a combination of glibenclamide and metformin in a 1:100 weightratio, so as to allow a daily dosage of 15 mg glibenclamide and 1500 mgmetformin, used for the onset of diabetes to the most severe cases,particular in cases of secondary failure to a combination ofglibenclamide-metformin HCl in a weight ratio higher than 1:100.

(2) Vigneri et al, Treatment of NIDDM Patients with Secondary Failure toGlyburide: Comparison of the Addition of Either Metformin or Bed-TimeNPH Insulin to Glyburide, Diabete & Metabolisme, 1991, 17, 232–234,disclose use of a combination of 1.5 g/day metformin and 15 mg/dayglyburide to treat NIDDM patients with secondary failure to 15 mg/dayglyburide.

(3) Higginbotham et al, Double-Blind Trial of Metformin in the Therapyof Non-Ketotic Diabetes, The Medical Journal of Australia, Aug. 11,1979, 154–156, discloses treatment of diabetic patients, who werealready receiving from 10 mg to 20 mg per day of glibenclamide, with 500mg metformin twice a day. Higginbotham et al conclude “that in selecteddiabetics whose condition is inadequately controlled with sulfonylureatherapy, significant improvement in diabetic control can be obtained bythe addition of metformin in a low dose of 500 mg twice a day.”

(4) U.S. application Ser. No. 09/353,141, filed Jul. 14, 1999 (based onEuropean application No. 98401781.4, filed Jul. 15, 1998) now U.S. Pat.No. 6,303,146 B1 discloses formulations containing metformin andglyburide where the glyburide is of a particular particle size.

Documents which disclose combinations of metformin and glipizide includethe following:

(1) Combination of glipizide/metformin treatment reduces low densitylipoprotein binding to arterial proteglycans in DIDDM, Edwards et al,Diabetes, (46, Suppl. 1, 45A, 1997).

(2) Combination of glipizide/metformin normalizes glucose and improvesinsulin sensitivity in hyperinsulinemia moderately well controlled.Cefalu et al, Diabetes, (45, Suppl. 2, 201A, 1996).

(3) Effects of combination of glipizide/metformin treatment onoxidizability of LDL in NIDDM, Crouse et al, Circulation, (94, No. 8,Suppl., I508, 1996).

(4) Insulin sensitivity is improved after glipizide monotherapy andcombination with metformin, Cefalu et al, Diabetologia, (39, Suppl. 1,A231, 1996).

(5) Combined Metformin—Sulfonylurea Treatment of Patients with NIDDM inFair to Poor Glycemic Control, Reaven et al, J. Clin. Endocrinol. Metab.(74, No. 5, 1020–26, 1992).

(6) Combination of Glipizide/Metformin Treatment in NIDDM, Hollenbeck etal, Diabetes, (39, Suppl. 1, 108A, 1990).

(7) Oral Antidiabetic Combination Therapy with Sulfonyl ureas andMetformin, Haupt et al, Med. Welt. (40, No. 5, 118–23, 1989).

(8) Variation of the lipemic pattern in diabetic subjects aftertreatment with a combination of glipizide and metformin, Ferlito et al,PROGR. MED. (Roma) 31/6 (289–301) 1975.

(9) Results with a combination of glipizide and dimethylbiguanide in 40cases of diabetes, Parodi et al, GAZZ. MED. ITAL. 132/5 (226–235) 1973.

(10) U.S. Pat. No. 6,099,862, Chen et al, “Oral Dosage Form for theControlled Release of a Biguanide and Sulfonylurea”.

Other combinations of metformin and another antidiabetic agent aredisclosed in documents that include the following:

(1) U.S. Pat. No. 5,631,224 to Efendic et al discloses a combination ofmetformin with GLP-1(7–36) amide or GLP-1(7–37) or a fragment thereof.

(2) WO 98/57634 (SKB) discloses a method for treating diabetes employinga combination of a thiazolidenedione and metformin. Thethiazolidenedione may be troglitazone, ciglitazone, pioglitazone orenglitazone, and may be employed in dosages of 2 to 12 mg per day whilethe metformin may be employed in daily dosages “of up to 3000 mg perday, in unit doses of 500 mg (for example, 2 to 3 times per day) or 850mg (2 times per day), one example of a dosage for metformin is 500 mgbuilding to 5 times per day.”

(3) EP 0749751A2 (Takeda) discloses a combination of a thiazolidenedioneinsulin sensitivity enhancer (such as pioglitazone) and metformin.

Several fixed combinations of metformin and glyburide (glibenclamide)are presently being marketed. These include (1) combinations of 400 mgmetformin/2.5 mg glibenclamide (Boehringer's Bi-Euglucon in Argentina,and Bi-Euglicon M in Italy; Guidotti/Menarini's Glibomet in theDominican Republic and Italy; HMR's Normell in Greece and Hoechst'sSuguan-M in Italy; Sun Pharma's Glucored in India; Monsanto's (Searle's)Benclamet in India; Guidotti's Glibomet in Liban; BerlinChemie/Menarini's Glibomet in the Slovak Rep., and Roche's Bi-Eugluconin Uruguay); (2) combinations of 500 mg metformin/5 mg glibenclamide(Sun Pharma's Glucored in India; Monsanto's (Searle's) Benclamet inIndia, USV's Duotrol in India; and Lakeside's (Roche) Bi-Euglucon M5 inMexico); (3) combinations of 500 mg metformin/2.5 mg glibenclamide(Molteni's Glucomide in Italy, Lakeside's (Roche) Bi-Euglucon M inMexico and Szabo's Dublex in Uruguay); (4) 1 g metformin/5 mgglibenclamide (Silanes Sil-Norboral in Mexico); and (5) Bristol-MyersSquibb's Glucovance®.

The labeling for Glucophage® (Bristol-Myers Squibb's metformin), in thePhysicians' Desk Reference 1999, under “Indications and Use”, indicatesthat Glucophage may be used concomitantly with a sulfonylurea. It isfurther indicated under “Dosage and Administration” “ConcomitantGlucophage and Oral Sulfonylurea Therapy” that “If patients have notresponded to four weeks of the maximum dose of Glucophage monotherapy,consideration should be given to gradual addition of an oralsulfonylurea while continuing Glucophage at the maximum dose . . . .With concomitant Glucophage and sulfonylurea therapy, the desiredcontrol of blood glucose may be obtained by adjusting the dose of eachdrug. However, attempts should be made to identify the maximum effectivedose of each drug to achieve this goal.” The recommended dosing schedulefor Glucophage® is a starting dose of 500 mg twice a day or 850 mg oncea day with dosage increases in increments of 500 mg weekly or 850 mgevery 2 weeks up to a total of 2000 mg per day.

Package inserts for Bi-Euglucon M and Suguan M in Italy (400 mgmetformin/2.5 mg glibenclamide) indicate that these drug combinationsare used in cases of primary or secondary resistance to sulfonyl ureas(that is as second or third line therapy) and that a dosage of ½ tabletper day increasing ½ tablet at a time according to glycemic variationsup to 4 tablets per day are employed.

Package inserts for Glibomet (400 mg metformin/2.5 mg glibenclamide) andGlucomide (500 mg metformin/2.5 mg glibenclamide) in Italy indicate thatthese drug combinations are used for treating type 2 diabetes which isnon-controllable or cannot be controlled with only diet or with diet andsulfonyl urea (that is as first line therapy or second line therapy).

The package insert for Glibomet in Italy indicates a daily dosage of 2tablets, that is 800 mg metformin and 5 mg glibenclamide, up to 2 gramsmetformin. The package insert for Glucomide in Italy indicates a dailydosage of 2 capsules, that is 1000 mg metformin up to 2 grams metformin,and 5 mg glibenclamide.

Thus, the concomitant use of metformin and a sulfonyl urea, includingglipizide, is known. However, the use of metformin and glipizide in asingle formulation in accordance with the present invention is notbelieved to be known in the art. Such a formulation would be highlydesirable for patient convenience and to ensure patient compliance, butpreparation of such a formulation also requires special care.

Commercially, metformin hydrochloride and glipizide are separatelyavailable as tablets. To prepare a metformin/glipizide combination in asingle tablet poses many challenges. First, the dose for each agent isvery different. Metformin is available commercially as 500 mg, 850 mgand 1000 mg tablets. Glipizide is available as 5 mg and 10 mg tablets.Moreover, glipizide is available as a micronized drug substance. Giventhe disparity in the doses of the agents and the differences in theirparticle sizes, content uniformity of glipizide poses significantproblems, especially when formulating glipizide with another agent likemetformin. Additionally, glipizide is susceptible to hydrolysis.Therefore, the amount of moisture must be controlled. However, at thesame time, some residual moisture is necessary to formulate tablets withsufficient hardness from metformin which is poorly compressible.Further, the selection of excipients must be made such that they arecompatible with both metformin and glipizide.

In view of the above, it is clear that it would be desirable to providemetformin and glipizide in a single formulation, but that preparation ofsuch a formulation requires special care that has not heretofore beenprovided in the art.

DESCRIPTION OF THE INVENTION

In accordance with the present invention, a pharmaceutical formulationis provided which includes a combination of metformin and glipizide in asingle formulation, wherein the glipizide content is uniform, and whichformulation controls moisture so that the glipizide does not hydrolyze,yet the metformin is compressable.

In addition, in accordance with the present invention, a method isprovided for treating diabetes, especially type 2 diabetes whichincludes the step of administering to a patient in need of treatment, atherapeutically effective pharmaceutical formulation of the inventionwhich includes a combination of metformin and glipizide in dosages asdescribed herein, in a single formulation wherein the glipizide contentis uniform, and which formulation controls moisture so that theglipizide does not hydrolyze, yet the metformin is compressable.

In addition, in accordance with the present invention, a method isprovided for decreasing fasting plasma glucose, decreasing insulinresistance, decreasing hemoglobin A1c, increasing post-prandial insulinand/or decreasing post-prandial glucose excursion in a human diabeticpatient, which includes the step of administering to a human patient thepharmaceutical formulation of the invention which includes a combinationof metformin/glipizide as described herein.

The pharmaceutical compositions of the present invention may take theform of several different embodiments. Thus, in one embodiment of thepresent invention, a pharmaceutical composition is provided wherein themetformin and glipizide are formulated together in a bilayered tabletwhich includes a first layer and a second layer. Glipizide, in the formof micronized particles will be present in the first layer together withoptional excipients as described hereinafter, while the metformin willbe present in the second layer which optionally may include one or moreexcipients as described hereinafter.

In addition, the bilayered tablet of the invention may include an outerprotective coating or finishing layer as described hereinafter.

Another embodiment of the present invention comprises a cored tabletwhich includes a core and a buffering layer or outer coat which can becompressed onto the core as a dry coat. The core will preferably includeglipizide particles while the buffering layer or outer coat will includemetformin together with one or more optional excipients.

The so-described cored tablet may also optionally include an outerprotective coating or finishing layer as described hereinafter.

In addition, in accordance with the present invention, a pharmaceuticalcomposition is provided which is in the form of a tablet or capsulewhich includes a mixture of glipizide particles having an entericcoating and metformin.

In yet another embodiment of the pharmaceutical composition of thepresent invention, enteric coated glipizide particle as described abovemay be further coated with a protective coating or finishing layer. Thedouble coated particles of glipizide can be mixed with metformin and themixture can be encapsulated or tableted as described herein. Theglipizide and the metformin do not need to be mixed together; these caneven be encapsulated separately into the same capsule shells in twoshots.

Another embodiment of the pharmaceutical composition of the inventionincludes particles of enteric coated glipizide and enteric coatedmetformin, in the same dosage form such as compressed tablets orcapsules.

The tablets containing the enteric coated particles of glipizide andmetformin may also include an outer protective coating or finishinglayer.

In a further embodiment of the pharmaceutical composition of theinvention, the composition of the invention may comprise a mixture ofglipizide particles and metformin; the above mixture may take the formof compressed tablets (which may be film coated) or capsules (where themixture can be encapsulated separately in two shots in the same capsuleshells).

Preferred daily dosages of the combination of metformin and glipizidewill be in the range from about 250 to about 2500 mg metformin,preferably in about 250 mg increments (e.g., 250, 500, 750, 1000, 1250,2000 and 2500 mg), and from about 1.25 to about 25 mg glipizide,preferably in about 2.25 mg increments (e.g., 1.25, 2.5, 5.0, 7.25,10.0, 12.5, 15.0, 20.0 and 250 mg). Especially preferred tabletstrengths include 250/1.25 mg, 250/2.5 mg, 500/2.5 mg and 500/5 mg.

DETAILED DESCRIPTION OF THE INVENTION

The term “diabetes” as employed herein, refers to type 2 (or Type II)diabetes or non-insulin dependent diabetes mellitus (NIDDM).

The term “metformin” as employed herein refers to metformin or apharmaceutically acceptable salt thereof such as the hydrochloride salt,the metformin (2:1) fumarate salt, and the metformin (2:1) succinatesalt as disclosed in U.S. Pat. No. 6,031,004, the hydrobromide salt, thep-chlorophenoxy acetate or the embonate, and other known metformin saltsof mono and dibasic carboxylic acids including those disclosed in U.S.Pat. No. 3,174,901, all of which salts are collectively referred to asmetformin. It is preferred that the metformin employed herein be themetformin hydrochloride salt, namely, that marketed as Glucophage®(trademark of Bristol-Myers Squibb Company).

The term “post-prandial excursion” as employed herein refers to thedifference between post-prandial glucose (PPG) and fasting plasmaglucose (FPG).

It is believed that the use of metformin in combination with glipizidein accordance with the present invention produces antihyperglycemicresults greater than that possible from each of these agents alone andgreater than the combined additive anti-hyperglycemic effects producedby these agents.

Metformin will be employed in a weight ratio to the glipizide in therange from about 2000:1 to about 10:1, preferably from about 400:1 toabout 100:1, more preferably from about 200:1 to about 100:1.

Glipizide may be employed in the formulation in amounts and dosing asindicated in the Physicians' Desk Reference.

In carrying out the present invention, pharmaceutical formulations orcompositions will be employed containing metformin and glipizide inassociation with a pharmaceutical vehicle or diluent. The formulationscan be formulated employing conventional solid or liquid vehicles ordiluents and pharmaceutical additives of a type appropriate to the modeof administration. The formulations of the invention can be administeredto mammalian species including humans, monkeys, dogs, etc., in the formof tablets or capsules. The dose can be administered in a single dose orin the form of individual doses from 1–4 times per day.

The above dosage forms may also include the necessary physiologicallyacceptable carrier material, excipient, lubricant, buffer,antibacterial, bulking agent (such as mannitol), anti-oxidants (ascorbicacid or sodium bisulfite) or the like.

The dose administered should be carefully adjusted according to the age,weight, and condition of the patient, as well as the dosage form andregimen, and the desired result.

The combination of the metformin or salt thereof and glipizide may beformulated separately or, where possible, in a single formulationemploying conventional formulation procedures.

The various formulations of the invention may optionally include one ormore fillers or excipients in an amount within the range of from about 0to about 90% by weight and preferably from about 1 to about 80% byweight such as lactose, sugar, corn starch, modified corn starch,mannitol, sorbitol, inorganic salts such as calcium carbonate and/orcellulose derivatives such as wood cellulose and microcrystallinecellulose.

One or more binders may be present in addition to or in lieu of thefillers in an amount within the range of from about 0 to about 35% andpreferably from about 0.5 to about 30% by weight of the composition.Examples of such binders which are suitable for use herein includepolyvinylpyrrolidone (molecular weight ranging from about 2500 to about3,000,000 and preferably about 50,000), lactose, starches such as cornstarch, modified corn starch, sugars, gum acacia and the like as well asa wax binder in finely powdered form (less than 500 microns) such ascarnauba wax, paraffin, spermaceti, polyethylenes or microcrystallinewax.

Tablets of the invention will include one or more tableting lubricantsin an amount within the range of from about 0.2 to about 8% andpreferably from about 0.5 to about 2% by weight of the composition, suchas magnesium stearate, stearic acid, palmitic acid, calcium stearate,talc, carnauba wax and the like. Other conventional ingredients whichmay optionally be present include preservatives, stabilizers,anti-adherents or silica flow conditioners or glidants, such as Syloidbrand silicon dioxide as well as FD&C colors.

Tablets of the invention may also include a coating layer which maycomprise from 0 to about 15% by weight of the tablet composition. Thecoating layer may comprise any conventional coating formulations andwill include one or more film-formers or binders, such as a hydrophilicpolymer like methylcellulose, and/or a hydrophobic polymer likemethacrylic acid esters neutral polymer, ethyl cellulose, celluloseacetate, polyvinyl alcohol-maleic anhydride copolymers, β-pinenepolymers, glyceryl esters of wood resins and the like and one or moreplasticizers, such as triethyl citrate, diethyl phthalate, propyleneglycol, glycerin, butyl phthalate, castor oil and the like. Both coretablets as well as coating formulations may contain aluminum lakes,titanium dioxide and/or iron oxides to provide color.

The film formers may be applied from a solvent system containing one ormore solvents including water, alcohols like methyl alcohol, ethylalcohol or isopropyl alcohol, ketones like acetone, or ethylmethylketone, chlorinated hydrocarbons like methylene chloride,dichloroethane, and 1,1,1-trichloroethane.

Where a color is employed, the color may be applied together with thefilm former, plasticizer and solvent compositions.

The finished dosage form is either a compressed tablet or a hard gelatincapsule, preferably a tablet. The tablet may be optionally film coated.The total amount of drug per dosage unit would be such as to offer adosage form of convenient size for patients. These tablets can, ofcourse, be scored to provide for fractional doses in some cases.

In forming the pharmaceutical composition of the invention in the formof a bilayered tablet, the first layer containing glipizide will alsopreferably include bulking agents such as lactose, microcrystallinecellulose, wood cellulose, corn starch, modified corn starch, calciumphosphate, sugar, dextrose, mannitol or sorbitol. The bulking agent willbe present in an amount from about 1 to about 90%, preferably from about5 to about 85% by weight of the first layer containing glipizide.

The first layer may also include a tableting lubricant, such as zincstearate, magnesium stearate, calcium stearate, talc, carnauba wax,stearic acid, palmitic acid or hydrogenated vegetable oils and fats, inan amount within the range from about 0.01 to about 4%, and preferably0.02 to about 2% by weight of the first layer.

The second layer of the bilayered tablet containing metformin willusually include a bulking agent such as lactose, microcrystallinecellulose, modified corn starch, calcium phosphate or other bulkingagent as set out above for the first layer, in an amount within therange from about 1 to about 90%, preferably from about 5 to about 85% byweight of the second layer. In addition, the second layer may include abinder such as corn starch, pregelatinized starch, polyvinyl pyrrolidone(PVP), hydroxypropylmethyl cellulose (HPMC), ethyl cellulose, celluloseacetate and the like, in an amount within the range from about 0.5 toabout 20%, preferably from about 1 to about 10% by weight of the secondlayer, and a tableting lubricant such as magnesium stearate, zincstearate, or other lubricant as set out above with respect to the firstlayer in an amount from about 0.01 to about 4%, preferably from about0.02 to about 2% by weight of the second layer.

The buffering agents present in the second layer may includeconventional acid buffers such as calcium carbonate, magnesium oxide,magnesium carbonate, magnesium hydroxide, aluminum hydroxide,dihydroxyaluminum sodium carbonate, aluminum magnesium hydroxide sulfateor aluminum hydroxide magnesium carbonate co-dried gel, or mixtures ofone or more thereof, in amounts as needed. Thus, amounts of bufferingagent within the range from about 10 to about 1000 mg, preferably fromabout 50 to about 500 mg will be employed depending upon the amount ofglipizide present in the first layer.

In forming a bilayered tablet of the invention, the first layercontaining glipizide may be prepared by conventional wet granulation ordry granulation (compaction) techniques.

The second layer containing metformin may be prepared by conventionalwet granulation or dry granulation (compaction) techniques.

The first and second layers may then be compressed and combined to forma bilayered tablet employing conventional bilayer tableting equipment.

Other conventional ingredients which may optionally be present in eitherof the two layers include preservatives, stabilizers, anti-adherents orsilica flow conditioners or glidants, such as Syloid brand silicondioxide as well as antioxidants such as Vitamin E, Vitamin C, and folicacid, Vitamin B₆ and Vitamin B₁₂.

The bilayer tablet of the invention may also include an outer protectivecoating layer which may comprise from 0 to about 15% by weight of thebilayer tablet. The outer protective coating layer which is applied overthe bilayered tablet may comprise any conventional coating formulationsand will include one or more film-formers or binders, such as ahydrophilic polymer like hydroxy-propylmethyl cellulose (HPMC) and ahydrophobic polymer like ethyl cellulose, cellulose acetate, polyvinylalcohol-maleic anhydride copolymers, acrylic copolymers, β-pinenepolymers, glyceryl esters of wood resins and the like, and one or moreplasticizers, such as polyethylene glycol, triethyl citrate, diethylphthalate, propylene glycol, glycerin, butyl phthalate, castor oil andthe like.

The film formers are applied from a solvent system containing one ormore solvents including water, alcohols like methyl alcohol, ethylalcohol or isopropyl alcohol, ketones like acetone, or ethylmethylketone, chlorinated hydrocarbons like methylene chloride,dichloroethane, and 1,1,1-trichloroethane.

The pharmaceutical composition of the invention in the form of a coredtablet wherein the glipizide forms the core, and metformin is present ina surrounding coat layer, may be prepared employing conventional coredtablet technology. Thus, the glipizide containing core (includingexcipients and other ingredients as described for the first layer in thebilayered tablet of the invention) may be formed in a manner similar tothe first layer of the bilayered tablet as described hereinbefore. Thelayer containing metformin as well as excipients and other ingredients(as described hereinbefore for the second layer of the bilayered tabletof the invention) may be compressed onto the core as a dry coat.

The so-formed cored tablet may be coated with an outer protectivecoating layer as described above for the bilayered tablet.

Another embodiment of the pharmaceutical composition of the invention isformed of tablets or capsules containing a mixture of enteric coatedglipizide particles and metformin.

The glipizide particles can be coated with conventional enteric polymercoatings in aqueous or non-aqueous systems. For example, EudragitL-30D-55 (acrylic acid copolymers-Rohm Pharma) (5 to 25% solids)containing 10 to 15% of diethylphthlate (w/w) as plasticizer can be usedin an aqueous system.

Other conventional enteric polymer coating systems may be employed suchas Eudragit R and S series resins, (acrylic acid copolymers-RohmPharma), cellulose acetate phthalate, cellulose acetate maleate,cellulose acetate succinate, hydroxypropylmethyl cellulose phthalate,hydroxypropylmethylcellulose acetate succinate, and the like, and asuitable plasticizer such as triethyl citrate, diethyl phthalate,tributyl citrate, triacetin, dibutyl phthalate dibutyl sebicate, Myvacet940, and other commonly used plasticizers as may be suitable for theparticular enteric polymers can be used. It will be appreciated that anypolymer with suitable plasticizer can be used in an aqueous ornon-aqueous system to form an enteric coating on the glipizide particle.

In another embodiment of the pharmaceutical composition of theinvention, the enteric coated glipizide particles described above may befurther coated with an outer protective finishing coat or layer asdescribed hereinbefore.

The double coated glipizide particles can be mixed with metformin andthe mixture can be encapsulated or tableted as described above.

In yet another embodiment of the pharmaceutical composition of theinvention, glipizide is enteric coated as described above and themetformin can optionally be enteric coated. The metformin can be coatedin the form of pure drugs or after spheronization or agglomeration. Theparticles for coating do not need to be perfectly spherical. These couldbe rods or irregular particles. The enteric coated particles of the twoagents (glipizide and metformin) can be tableted or encapsulatedtogether. As described above, appropriate excipients (fillers, binders,disintegrants, and lubricant, etc.) can be used to facilitate tableting.

In yet another embodiment, glipizide particles can be mixed with entericcoated particles of metformin, and the mixture can be tableted orencapsulated, or the two granules can be encapsulated in two shots inthe same capsule shells.

In still a further embodiment, neither the glipizide particles nor themetformin particles need to be enteric coated.

Examples of typical ingredients are shown in Table 1.

Examples of typical ingredients used in manufacturingmetformin/glipizide combination tablets is shown below in Table 1.Included in the table are alternative ingredients as well as commonlyused ranges.

Commonly used amounts Ingredient Function Alternatives (% w/w) MetforminActive 50% to 95% ingredient Glipizide Active 0.1% to 2.5% ingredientMicrocrystal- Diluent Lactose, calcium  1% to 60% line cellulosephosphate, mannitol Povidone Binder Hydroxypropyl 0.5% to 10% cellulose, methyl- cellulose, hydroxypropyl- methylcellulose, starch,gelatin, guar gum, zanthum gum, pregelati- nized starch CroscarmelloseDisintegrant Crospovidone, 0.5% to 10%  sodium sodium starch glycolate,pregelatinized starch, starch Magnesium Lubricant Stearic acid, 0.1% to5%   stearate calcium stearate, zinc stearate, sodium stearyl fumarateHPMC Coating Ethyl cellulose, 0.5% to 10%  methacrylic copolymers,hydroxypropyl cellulose Water Granulating Ethanol, methanol Used for theand coating process; solvent removed by drying

The preferred pharmaceutical formulations of the invention in the formof a tablet may be obtained generally by a process which includes thesteps of

-   -   a) forming granules by wet granulation of a mixture of metformin        and glipizide with some of the excipients (e.g.,        microcrystalline cellulose, povidone and croscarmellose sodium),    -   b) blending the granules with additional microcrystalline        cellulose and magnesium stearate and diluent, and    -   c) tableting the blend thus obtained into tablets.

The mixture used for forming the granules may include a granulatingbinder. The granulating binder is preferably a polyvinylpyrrolidone suchas, for example, a polyvinylpyrrolidone having a molecular weight of50,000. The polyvinylpyrrolidone may be used in a proportion of 2 to 4%by weight with respect to the final tablet.

After the granulating step, the granules may be sieved and dried.

The granules may then be blended with a diluent and tableting aid. Thediluent may be a conventional filler usually used for making tablets,such as microcrystalline cellulose. The tableting aid may be aconventional material, such as magnesium stearate.

The tablets thus obtained may then optionally be coated with ahydrophilic cellulose polymer and talc. The hydrophilic cellulosepolymer is preferably 2-hydroxypropyl methylcellulose.

Typical formulations for metformin/glipizide film coated tablets ofdifferent strengths appear below in table 2.

TABLE 2 Metformin/glipizide Ingredients 500/2.5 mg 500/5 mg 250/2.5 mg500/7.5 mg 250/1.25 mg 500/1.25 mg Tablet Core mg/tab %, w/w mg/tab %,w/w mg/tab %, w/w mg/tab %, w/w mg/tab %, w/w mg/tab %, w/w Metformin502.5 83.75 502.5 83.75 251.25 83.75 502.5 83.75 251.25 83.75 502.583.75 Hydrochloride with 0.5% Mg Stearate Premix Glipizide 2.5 0.417 5.00.834 2.5 0.834 7.5 1.250 1.25 0.417 1.25 0.208 Croscarmellose 14 2.3314 2.33 7 2.33 14 2.33 7 2.33 14 2.33 Sodium NF Povidone 20 3.33 20 3.3310 3.33 20 3.33 10 3.33 20 3.33 Purified q.s. q.s. q.s. q.s. q.s. q.s.Water^(A) Micro- 56.5 9.42 54.0 9.00 27 9.00 51.5 8.58 28.25 9.42 57.759.63 crystalline Cellulose NF Magnesium 4.5 0.75 4.5 0.75 2.25 0.75 4.50.75 2.25 0.75 4.5 0.75 Stearate NF TOTAL TAB- 600 100 600 100 300 100600 100 300 100 600 100 LET CORE Film Coating^(B) Opadry White 21 3.510.5 3.5 21 3.5 Opadry Pink 21 3.5 10.5 3.5 32K14883 (lighter) OpadryPink 21 3.5 YS-1-14778-A (darker) Purified 119 119 59.5 119 Water^(A)Total Tablet 621 621 310.5 621 310.5 621.0 Weight Note: ^(A)Water wasremoved during processing. ^(B)The actual amount of coating may varybased on a range of 3.0–4.0% of the film coat.

In whatever embodiment, the formulation is typically administered so asto provide from about 250 to about 500 mg metformin one to four timesdaily. The glipizide will preferably be administered in an amount fromabout 1.25 to about 5.0 mg one to four times daily, with a maximum of upto about 20.0 mg daily.

The pharmaceutical formulation of the invention is an adjunct to dietand exercise to improve glycemic control in patients with type 2diabetes mellitus.

The ADA recommends a treatment goal of HbA_(1c)<7% (ADA. Diabetes Care21 [Suppl. 1]: S23–S31, 1998) in order to reduce the risk ofcomplications of type 2 diabetes mellitus, including coronary heartdisease and microvascular complications.

Dosage of the formulation of the invention must be individualized on thebasis of both effectiveness and tolerance. It is preferably given withmeals and should be started at a low dose, with gradual dose escalation.Ideally, the response to therapy should be evaluated using HbA_(1c)(glycosylated hemoglobin) which is a better indicator of long-termglycemic control than FPG (fasting plasma glucose) alone. Thetherapeutic goal in all patients with type 2 diabetes mellitus should beto improve glycemic control, including FPG, postprandial glucose andHbA_(1c) levels, to normal or as near normal as possible. Patientsshould be titrated to achieve the ADA goal of HbA_(1c)<7% following thedosing recommendations up to the maximum recommended dose. (ADA.Diabetes Care 21 [Suppl. 1]: S23–S32, 1998).

For patients with type 2 diabetes whose hyperglycemia cannot besatisfactorily managed with diet and exercise alone, the recommendedstarting dose is 2.5 mg/250 mg once a day with a meal. As initialtherapy in patients with baseline FPG>280 mg/dL, a starting dose of 2.5mg/500 mg once daily should be considered. Dosage increases to achieveadequate glycemic control should be made in increments of one tablet perday every two weeks up to a maximum of approximately 10 mg/1000 mg or 10mg/2000 mg per day given in divided doses.

For patients not adequately controlled on either glipizide (or anothersulfonylurea) or metformin alone, the recommended starting dose is 2.5mg/500 mg or 5 mg/500 mg twice daily with the morning and evening meals.In order to avoid hypoglycemia, the starting dose should not exceed thedaily doses of glipizide or metformin already being taken. The dailydose should be titrated in increments of no more than 5 mg/500 mg up tothe minimum effective dose to achieve adequate control of blood glucoseor to a maximum dose of about 20 mg/2000 mg per day.

For patients previously treated with combination therapy of glipizide(or another sulfonylurea) plus metformin, the starting dose should notexceed the daily dose of glipizide (or equivalent dose of anothersulfonylurea) and metformin already being taken. The decision to switchto the nearest equivalent dose or to titrate should be based on clinicaljudgment. Patients should be monitored closely for signs and symptoms ofhypoglycemia following such a switch and the dose should be titrated toachieve adequate control of blood glucose.

EXAMPLE

Tablets containing metformin/glipizide combinations were prepared asdescribed below for 250 mg/2.5 mg:

Batch formula, Metformin HCl/glipizide tablet, 250/2.5 mg Materialsmg/tab. Gram/5 kg batch Intragranular Metformin HCl w 0.5% MgS 251.254187.5 Glipizide 2.5 41.666 Croscarmellose sodium 7.0 116.7 Povidone(PVP) 10.00 166.7 Water^(A) q.s. q.s. Extragranular Microcrystallinecellulose 27.0 450.0 (PH-102 grade) Magnesium Stearate 2.25 37.5 CoreTablet Weight 300.0 5000.0 Film Coating Opadry Pink 32K14883 10.5 175.0Water q.s. q.s. Total Tablet Weight 310.5 5175.0 ^(A)Water is used forgranulation and removed by drying from the tablets. ^(B)Removed duringcoating.

Croscarmellose sodium and glipizide were dispersed together followed byblending with about 790 g metformin hydrochloride/magnesium stearate(99.5%:0.5% w/w) in a mixer at low speed for 10 minutes. About ½ of thedry mix, ½ of the remaining metformin, the other ½ of the dry 15 mix andthe final ½ of the metformin were layered in the mixer and mixed for anadditional 10 minutes. The resultant dry mix was granulated in a highshear mixer with an aqueous povidone solution and granules were dried ina fluid bed dryer at approximately 40° C. with the residual moisturebetween about 2.0% and 3.0% w/w. The dried granulation was reduced witha #18 mesh screen oscillator or a comil and mixed with themicrocrystalline cellulose in a V-blender. Magnesium stearate was addedinto the V-blender and blended for 5 minutes.

The resultant blend was compressed into tablets on a suitable tabletpress.

The tablets were then preheated in a perforated coating pan at 40° C. to60° C. for 15 minutes. Then the coating pan was rotated at 4 to 8 rpmand the spraying of the film coating begun. When the coating wasapproximately 3.5%, the spray was stopped. The pan was allowed to rotateuntil the tablets cooled down.

If the granules were oven-dried during the drying process, they werere-wetted by spraying a calculated amount of water in a mixer. Themoisture in the granules should be 2% to 3% w/w to make tablets withacceptable hardness and to prevent caping.

During the coating process, tablets are preheated to drive the excessmoisture out and to harden the tablets so that tablets will not crumblewhen rotated in the coating pan. The reduction of the moisture is alsoused to minimize hydrolysis of glipizide. Once the coating is appliedand dried, the coating layer will act as a barrier against moisture andwill minimize the hydrolysis of glipizide.

1. A pharmaceutical composition comprising a single dosage formulationof metformin and glipizide said formulation containing from 2 to 3% byweight moisture, said formulation being in the form of a tablet designedto control moisture so that the glipizide does not hydrolyze and saidmetformin is compressible, said tablet further including an outerprotective coating or finishing layer surrounding said tablet, saidcomposition being devoid of an enteric coating.
 2. The pharmaceuticalformulation as defined in claim 1 which includes a dosage of metforminof from about 250 to about 2500 mg glipizide from about 1.25 to about 25mg/day.
 3. The pharmaceutical formulation as defined in claim 1 whereinthe metformin is employed in a weight ratio to the glipizide within therange from about 1000:1 to about 100:1.
 4. The pharmaceuticalformulation as defined in claim 1 wherein the dosage of metformin is 250mg and the dosage of glipizide is 1.25 mg.
 5. The pharmaceuticalformulation as defined in claim 1 wherein the dosage of metformin is 250mg and the dosage of glipizide is 2.50 mg.
 6. The pharmaceuticalformulation as defined in claim 1 wherein the dosage of metformin is 500mg and the dosage of glipizide is 2.50 mg.
 7. The pharmaceuticalformulation as defined in claim 1 wherein the dosage of metformin is 500mg and the dosage of glipizide is 5.00 mg.